Novel acyclic chiral derivatives of hibiscus acid and the process of preparing the same

ABSTRACT

The present invention relates to a novel acyclic chiral derivatives of Hibiscus acid of formula I,  
                 
 
     wherein:  
     R 1 ═R 5 ═lower aryl or alkyl ester or substituted aryl or alkyl alcohol R 3 ═substituted aryl or alkyl ester or substituted aryl alcohol R 2 ═R4═hydroxyl or  
                 
 
     and a process for preparing the same.

[0001] This invention relates to novel acyclic chiral derivatives ofhibiscus acid and the process of preparing the same.

BACKGROUND OF THE INVENTION

[0002] Hibiscus acid, [(+)-Hydroxycitric acid lactone or (2S,3R)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid], can beisolated from the leaves /fruit calyxes of Hibiscus sabdariffa or fromthe leaves of Hibiscus furcatus, and Hibiscus cannabinus. However thenon-availability of Hibiscus acid in the market, in the optically pureform, has resulted in the limited use of Hibiscus acid or itsderivatives in the broad area of organic synthesis and pharmaceuticalfront. In U.S. patent application No. 09/365,300, the large scalemanufacture of Hibiscus acid in the optically pure crystalline form hasbeen described.

[0003] During the past two decades there has been a great deal ofinterest in finding cheap and potential chiral derivatives from chiralpool to accomplish synthetic pathways with a high degree of asymmetricinduction.

[0004] The object of the present invention is to synthesize novelacyclic chiral derivatives of Hibiscus acid which are found to beimportant building blocks in organic synthesis and are extensively usedfor the preparation of optically active ligands and biologically activeproducts.

[0005] To achieve the said objective this invention provides a novelacyclic chiral compound of Hibiscus acid of formula I,

[0006] wherein:

[0007] R₁═R₅═lower aryl or alkyl ester or substituted aryl or alkylalcohol R₃═substituted aryl or alkyl ester or substituted aryl alcoholR₂═R₄═hydroxyl or

[0008] In the above formula I:

[0009] R₁& R₅ is selected from —COOCH₃, —COOC₂H₅, —COOCH(CH₃)₂,—C(Ph)₂OH, —C(4-MePh)₂OH, —C(1-Naphth)₂OH R₂and R₄ is OH or

[0010] R₃ is selected from —CH₂COOCH₃, —CH₂COOC₂H₅, —CH₂COOCH(CH₃)₂,—CH₂C(Ph)₂OH, —CH₂C(4-MePh)₂OH, —CH₂C(1-Naphth)₂OH to form variouschiral derivatives, namely, chiral triesters, chiral ketals, chiralalcohols.

[0011] Chiral Triester derivatives:

[0012] Ia- R₁═R₅═—COOCH₃, R₂═R₄═—OH and R₃═—CH₂COOCH₃

[0013] Ib- R₁═R₅═—COOC₂H₅, R₂═R₄═—OH R₃═—CH₂COOC₂H₅

[0014] Ic- R₁═R₅═—COOCH(CH₃)₂, R₂═R₄═—OH and R₃═—CH₂COOCH(CH₃)₂

[0015] Chiral Ketal derivatives:

[0016] Chiral Alcohol derivatives(diols):

[0017] Compound of formula Ia is trimethyl(1S,2R)-1,2-dihydroxy-1,2,3-propanetricarboxylate

[0018] Compound of formula Ib is Triethyl(1S,2R)-1,2-dihydroxy-1,2,3-propanetricarboxylate.

[0019] Compound of formula Ic is Tri isopropyl(1S,2R)-1,2-dihydroxy-1,2,3-propanetricarboxylate.

[0020] Compound of formula Id isdimethyl(4S,5R)-2,2-dimethyl-4-(2-oxo-2-methoxyethyl)-1,3-dioxolane-4,5-dicarboxylate(Id)

[0021] Compound of formula Ie is diethyl(4S,5R)-2,2-dimethyl-4-(2-oxo-2-ethoxyethyl)-1,3-dioxolane-4,5-dicarboxylate (Ie)

[0022] Compound of formula If is(4S,5R)-4-(2-hydroxy-2,2-diphenylethyl)-2,2-dimethyl-alpha,alpha,alpha′,alpha′-tetraphenyl-1,3-dioxolane-4,5-dimethanol (If).

[0023] The present invention further includes a process for preparingthe acyclic chiral triester of formulae Ia-Ic comprising

[0024] refluxing hibiscus acid with appropriate alcohol in presence ofan inorganic catalyst for 6-12 hours,

[0025] adjusting the pH of the reaction mixture to neutral using aqueousalkali solution,

[0026] concentrating the said reaction-mixture by evaporation,

[0027] extracting the said concentrate with an organic solvent,

[0028] concentrating the said extract to yield the said product.

[0029] The said appropriate alcohols are selected from methanol, ethanoland isopropanol.

[0030] The said catalyst is conc. HCl and said organic solvent ischloroform.

[0031] The present invention also includes a process for preparing theacyclic chiral triester of formulae If-Ih comprising:

[0032] adding solution of chiral acetal/ketal in an organic solvent to asoution of appropriate grignard reagent(ArMgX) in an organic solvent,

[0033] refluxing the mixture for 10-20 hours,

[0034] adding the inorganic salt solution to the chilled reactionmixture,

[0035] collecting the organic phase and extracting the aqueous layerfurther with a suitable organic acid,

[0036] drying the organic extract using a suitable salt,

[0037] evaporating the said extract,

[0038] subjecting the residue to chromatography.

[0039] The organic solvent is tetra hydro furan (THF).

[0040] The said appropriate grignard reagent is phenyl Mg bromide,methylphenyl Mg bromide, naphthyl Mg bromide.

[0041] The said inorganic salt is ammonium chloride.

[0042] The said organic solvent used for extraction is ether.

[0043] The said salt used for drying the extract is sodium sulphate.

[0044] The chromatography employed for purification is columnchromatography. The gel used for chromatography is silica gel. Theeluant used for chromatography is hexane chloroform mixture.

[0045] Summary of the chiral derivatives of Hibiscus acid is given belowin scheme I:

[0046] Standard procedures are followed for the preparation of variouschiral ketals of the type Id and Ie.

[0047] The invention will now be described with reference to theforegoing examples:

EXAMPLE 1 Trimethyl (1S,2R)-1,2-dihydroxy-1,2,3-propanetricarboxylate(Ia):

[0048] Hibiscus acid (1.0 g, 5 mmol) was refluxed with methanol (10 ml)and conc. HCl (0.4 ml) for 12 hours. pH of the reaction mixture wasadjusted to neutral using aqueous solution of sodium bicarbonate. Theresultant solution was evaporated and extracted with chloroform (4×20ml). The combined chloroform extracts was dried (sodium sulphate) and onconcentration furnished Ia. Yield: 0.5 g (38% ).

EXAMPLE 2 Triethyl (1S,2R)-1,2-dihydroxy-1,2,3-propanetricarboxylate(Ib):

[0049] Ib was prepared from Hibiscus acid and ethanol in 39% yield bythe same procedure used to prepare Ia from Hibiscus acid.

EXAMPLE 3 Triisopropyl (1S,2R)-1,2-dihydroxy-1,2,3-propanetricarboxylate(Ic):

[0050] Ic was prepared from Hibiscus acid and dry isopropanol by thesame procedure used to prepare Ia from Hibiscus acid Meltingpoint: 110°C. Yield: 4.0 g (66%)

EXAMPLE 4Dimethyl(4R,5S)-2,2-dimethyl-4-(2-oxo-2-methoxyethyl)-1,3-dioxolane-4,5-dicarboxylate(Id):

[0051] To Ia (1.0 g, 4 mmol) in dry acetone (25 ml), anhydrous coppersulphate (1.0 g) and a few drops of conc. sulphuric acid were added. Themixture was refluxed for four hours, followed by filtration andneutralisation using aqueous sodium bicarbonate solution. The resultantsolution obtained after evaporation was extracted with hexane (4×20 ml).The combined extracts after washing with water (50 ml) was dried withsodium sulphate. Upon evaporation, Id obtained as an yellow oil. Yield:0.4g (35%)

EXAMPLE 5 Diethyl(4R,5S)-2,2-dimethyl-4-(2-oxo-2-ethoxyethyl)-1,3-dioxolane-4,5-dicarboxylate(Ie):

[0052] Ie was prepared from Ib in 53% yield by the same procedure usedto prepare Id from Ia.

EXAMPLE 6 (4R,5S)-4-(2-hydroxy-2,2-diphenylethyl)-2,2-dimethyl-alpha,alpha,alpha′,alpha′-tetraphenyl-1,3-dioxolane-4,5-dimethanol (If):

[0053] A solution of Id (0.5g, 1.7 mmol, in 5 ml THF) was added to asolution of Phenyl magnesium bromide in THF (10 ml, 1M) and the mixturewas refluxed for 15 hours. To the chilled reaction mixture aqueousammonium chloride solution (20 ml) was added. The organic phase wascollected and the aqueous layer was extracted with ether (5×10 ml). Theorganic phase and the ether extracts were combined and dried (sodiumsulphate). The solution upon evaporation followed by columnchromatography (silica gel 60-120 mesh, eluent: hexane) yielded If.Yield: 0.5 g (44%)

[0054] USES:

[0055] Pharmaceutical applications

[0056] Chiral derivatives Ia-Ic and If-Ih is used for the preparation ofchiral catalyst and chiral auxiliaries.

[0057] The derivatives of Ia-Ih is used as chiral synthons

We claim:
 1. A novel acyclic chiral compound of Hibiscus acid of formula I,

wherein: R₁═R₅═lower aryl or alkyl ester or substituted aryl or alkyl alcohol R₃ ═substituted aryl or alkyl ester or substituted aryl alcohol R₂ ═R4═hydroxyl or


2. A compound as claimed in claim 1 wherein, R₁ & R₅ is selected from —COOCH₃, —COOC₂H₅, —COOCH(CH₃)₂, —C(Ph)₂OH, —C(4-MePh)₂OH, 13 C(1-Naphth)₂OH R₂and R4is OH or

R₃ is selected from —CH₂COOCH₃, —CH₂COOC₂H₅, —CH₂COOCH(CH₃)₂, —CH₂C(Ph)₂OH, —CH₂C(4-MePh)₂OH, —CH₂C(1-Naphth)₂OH
 3. A compound as claimed in claim 2 wherein, R₁═R₅═—COOCH₃, R₂═R4═—OH and R₃═—CH₂COOCH₃and said compound is trimethyl (1S,2R)-1,2-dihydroxy-1,2,3-propanetricarboxylate.


4. A compound as claimed in claim 2 wherein R₁═R₅═—COOC₂H₅, R₂═R4═—OH R₃═—CH₂COOC₂H₅ and said compound is Triethyl (1S,2R)-1,2-dihydroxy-1,2,3-propanetricarboxylate.


5. A compound as claimed in claim 2 wherein R₁═R₅═—COOCH(CH₃)₂, R₂═R₄═—OH and R₃═—CH₂COOCH(CH₃)₂ and said compound is Tri isopropyl (1S,2R)-1,2-dihydroxy-1,2,3-propanetricarboxylate.


6. A compound as claimed in claim 2 wherein

R₁═R₅═—COOCH₃ , R₃═—CH₂COOCH₃)₂ and said compound is dimethyl(4S,5R)-2,2-dimethyl-4-(2-oxo-2-methoxyethyl)-1,3-dioxolane-4,5-dicarboxylate.


7. A compound as claimed in claim 2 wherein

R₁═R₅═—COOC₂H₅ and R₃═—CH₂COOC₂H₅ and said compound is diethyl (4S,5R)-2,2-dimethyl-4-(2-oxo-2-ethoxyethyl)-1,3-dioxolane-4,5-dicarboxylate.


8. A compound as claimed in claim 2 wherein

R₁═R₅═—C(Ph)₂OH and R₃═—CH₂C(Ph)₂OH and said compound (4S,5R)-4-(2-hydroxy-2,2-diphenylethyl)-2,2-dimethyl-alpha, alpha,alpha′,alpha′-tetraphenyl-1,3-dioxolane-4,5-dimethanol


9. A compound as claimed in claim 2 wherein

R₁═R₅═—C(4-MePh)₂OH and R₃═—CH₂C(4-MePh)₂OH and said compound


10. A compound as claimed in claim 2 wherein R₂, R₄═

R₁═R₅═—C(1-Naphth)₂OH and R₃═—CH₂C(1-Naphth)₂OH


11. A process for preparing the acyclic chiral triester of formulae Ia-Ic of as claimed in claim 1 comprising refluxing hibiscus acid with appropriate alcohol in presence of an inorganic catalyst for 6-12 hours, adjusting the pH of the reaction mixture to neutral using aqueous alkali solution, concentrating the said reaction-mixture by evaporation, extracting the said concentrate with an organic solvent, concentrating the said extract to yield the said product.
 12. A process as claimed in claim 11 wherein, the said appropriate alcohols are selected from methanol, ethanol and isopropanol.
 13. A process as claimed in claim 1 wherein, the said catalyst is conc. HCl.
 14. A process as claimed in claim 1 wherein, the said organic solvent is chloroform.
 15. A process for preparing compounds of formulae If-Ih as claimed in claim 1 comprising: adding solution of chiral acetal/ketal in an organic solvent to a soution of appropriate grignard reagent(ArMgX) in an organic solvent, refluxing the mixture for 10-20 hours, adding the inorganic salt solution to the chilled reaction mixture, collecting the organic phase and extracting the aqueous layer further with a suitable organic acid, drying the organic extract using a suitable salt, evaporating the said extract, subjecting the residue to chromatography.
 16. A process as claimed in claim 15 wherein, the organic solvent is tetra hydro Fran (THF).
 17. A process as claimed in claim 15 wherein, the said appropriate grignard reagent is phenyl Mg bromide, methylphenyl Mg bromide, naphthyl Mg bromide.
 18. A process as claimed in claim 15 wherein, the said inorganic salt is ammonium chloride.
 19. A process as claimed in claim 15 wherein, the said organic solvent used for extraction is ether.
 20. A process as claimed in claim 15 wherein, the said salt used for drying the extract is sodium sulphate.
 21. A process as claimed in claim 15 wherein, the chromatography employed for purification is column chromatography.
 22. A process as claimed in claim 21 wherein, the gel used for chromatography is silica gel.
 23. A process as claimed in claim 22 wherein, the eleunt used for chromatography is hexane chloroform mixture. 